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Nicolien T van Ravesteyn,
Diana L Miglioretti,
Natasha K Stout, Sandra J Lee,
Clyde B Schechter,
Diana S M Buist,
Hui Huang,
Eveline A M Heijnsdijk,
Amy Trentham-Dietz,
Oguzhan Alagoz,
Aimee M Near,
Karla Kerlikowske,
Heidi D Nelson,
Jeanne S Mandelblatt,
Harry J de Koning
[show abstract]
[hide abstract]
ABSTRACT: Timing of initiation of screening for breast cancer is controversial in the United States.
To determine the threshold relative risk (RR) at which the harm-benefit ratio of screening women aged 40 to 49 years equals that of biennial screening for women aged 50 to 74 years.
Comparative modeling study.
Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and medical literature.
A contemporary cohort of women eligible for routine screening.
Lifetime.
Societal.
Mammography screening starting at age 40 versus 50 years with different screening methods (film, digital) and screening intervals (annual, biennial).
Benefits: life-years gained, breast cancer deaths averted; harms: false-positive mammography findings; harm-benefit ratios: false-positive findings/life-years gained, false-positive findings/deaths averted.
Screening average-risk women aged 50 to 74 years biennially yields the same false-positive findings/life-years gained as biennial screening with digital mammography starting at age 40 years for women with a 2-fold increased risk above average (median threshold RR, 1.9 [range across models, 1.5 to 4.4]). The threshold RRs are higher for annual screening with digital mammography (median, 4.3 [range, 3.3 to 10]) and when false-positive findings/deaths averted is used as an outcome measure instead of false-positive findings/life-years gained. The harm-benefit ratio for film mammography is more favorable than for digital mammography because film has a lower false-positive rate.
The threshold RRs changed slightly when a more comprehensive measure of harm was used and were relatively insensitive to lower adherence assumptions.
Risk was assumed to influence onset of disease without influencing screening performance.
Women aged 40 to 49 years with a 2-fold increased risk have similar harm-benefit ratios for biennial screening mammography as average-risk women aged 50 to 74 years. Threshold RRs required for favorable harm-benefit ratios vary by screening method, interval, and outcome measure.
National Cancer Institute.
Annals of internal medicine 05/2012; 156(9):609-17. · 16.73 Impact Factor
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Jeanne S Mandelblatt,
Kathleen A Cronin,
Donald A Berry,
Yaojen Chang,
Harry J de Koning, Sandra J Lee,
Sylvia K Plevritis,
Clyde B Schechter,
Natasha K Stout,
Nicolien T van Ravesteyn,
Marvin Zelen,
Eric J Feuer
[show abstract]
[hide abstract]
ABSTRACT: Optimal US screening strategies remain controversial. We use six simulation models to evaluate screening outcomes under varying strategies.
The models incorporate common data on incidence, mammography characteristics, and treatment effects. We evaluate varying initiation and cessation ages applied annually or biennially and calculate mammograms, mortality reduction (vs. no screening), false-positives, unnecessary biopsies and over-diagnosis.
The lifetime risk of breast cancer death starting at age 40 is 3% and is reduced by screening. Screening biennially maintains 81% (range 67% to 99%) of annual screening benefits with fewer false-positives. Biennial screening from 50-74 reduces the probability of breast cancer death from 3% to 2.3%. Screening annually from 40 to 84 only lowers mortality an additional one-half of one percent to 1.8% but requires substantially more mammograms and yields more false-positives and over-diagnosed cases.
Decisions about screening strategy depend on preferences for benefits vs. potential harms and resource considerations.
Breast (Edinburgh, Scotland) 10/2011; 20 Suppl 3:S75-81. · 2.09 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The high prevalence of HIV-1/AIDS in areas endemic for schistosomiasis and other helminthic infections has led to the hypothesis that parasites increase host susceptibility to immunodeficiency virus infection. We previously showed that rhesus macaques (RM) with active schistosomiasis were significantly more likely to become systemically infected after intrarectal (i.r.) exposure to an R5-tropic clade C simian-human immunodeficiency virus (SHIV-C) than were parasite-free controls. However, we could not address whether this was due to systemic or mucosal effects. If systemic immunoactivation resulted in increased susceptibility to SHIV-C acquisition, a similarly large difference in host susceptibility would be seen after intravenous (i.v.) SHIV-C challenge. Conversely, if increased host susceptibility was due to parasite-induced immunoactivation at the mucosal level, i.v. SHIV-C challenge would not result in significant differences between parasitized and parasite-free monkeys.
We enrolled two groups of RM and infected one group with Schistosoma mansoni; the other group was left parasite-free. Both groups were challenged i.v. with decreasing doses of SHIV-C. No statistically significant differences in 50% animal infectious doses (AID(50)) or peak viremia were seen between the two groups. These data strongly contrast the earlier i.r. SHIV-C challenge (using the same virus stock) in the presence/absence of parasites, where we noted a 17-fold difference in AID(50) and one log higher peak viremia in parasitized monkeys (P<0.001 for both). The lack of significant differences after the i.v. challenge implies that the increased host susceptibility is predominantly due to parasite-mediated mucosal upregulation of virus replication and spread, rather than systemic effects.
The major impact of schistosome-induced increased host susceptibility is at the mucosal level. Given that >90% of all new HIV-1 infections worldwide are acquired through mucosal contact, parasitic infections that inflame mucosae may play an important role in the spread of HIV-1.
PLoS Neglected Tropical Diseases 08/2011; 5(8):e1270. · 4.69 Impact Factor
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Samir K Lakhashe,
Vijayakumar Velu,
Gaia Sciaranghella,
Nagadenahalli B Siddappa,
Janet M Dipasquale,
Girish Hemashettar,
John K Yoon,
Robert A Rasmussen,
Feng Yang, Sandra J Lee, [......],
Rama Rao Amara,
Maria Kahn,
Shiu-Lok Hu,
Sufen Li,
Zhongxia Li,
Fred R Frankel,
Marjorie Robert-Guroff,
Welkin E Johnson,
Judy Lieberman,
Ruth M Ruprecht
[show abstract]
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ABSTRACT: We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus > 90%; these RM also had strong SIV Gag-specific proliferation of CD8⁺ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4⁺ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection.
Vaccine 06/2011; 29(34):5611-22. · 3.77 Impact Factor
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Samir K Lakhashe,
Wendy Wang,
Nagadenahalli B Siddappa,
Girish Hemashettar,
Patricia Polacino,
Shiu-Lok Hu,
François Villinger,
James G Else,
Francis J Novembre,
John K Yoon, Sandra J Lee,
David C Montefiori,
Ruth M Ruprecht,
Robert A Rasmussen
[show abstract]
[hide abstract]
ABSTRACT: A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time.
PLoS ONE 01/2011; 6(7):e22010. · 4.09 Impact Factor
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Agnès L Chenine,
Nagadenahalli B Siddappa,
Victor G Kramer,
Gaia Sciaranghella,
Robert A Rasmussen, Sandra J Lee,
Michael Santosuosso,
Mark C Poznansky,
Vijayakumar Velu,
Rama R Amara,
Chris Souder,
Daniel C Anderson,
François Villinger,
James G Else,
Francis J Novembre,
Elizabeth Strobert,
Shawn P O'Neil,
W Evan Secor,
Ruth M Ruprecht
[show abstract]
[hide abstract]
ABSTRACT: Worldwide, approximately 90% of all human immunodeficiency virus (HIV) transmissions occur mucosally; almost all involve R5 strains. Risks of sexual HIV acquisition are highest for rectal, then vaginal, and finally oral exposures.
Mucosal lacerations may affect the rank order of susceptibility to HIV but cannot be assessed in humans. We measured relative virus transmissibility across intact mucosae in macaques using a single stock of SHIV-1157ipd3N4, a simian-human immunodeficiency virus encoding a primary R5 HIV clade C env (SHIV-C).
The penetrability of rhesus macaque mucosae differed significantly, with rectal challenge requiring the least virus, followed by vaginal and then oral routes (P = .031, oral vs vaginal; P < .001 rectal vs vaginal). These findings imply that intrinsic mucosal properties are responsible for the differential mucosal permeability. The latter paralleled the rank order reported for humans, with relative risk estimates within the range of epidemiological human studies. To test whether inflammation facilitates virus transmission--as predicted from human studies--we established a macaque model of localized buccal inflammation. Systemic infection occurred across inflamed but not normal buccal mucosa.
Our primate data recapitulate virus transmission risks observed in humans, thus establishing R5 SHIV-1157ipd3N4 in macaques as a robust model system to study cofactors involved in human mucosal HIV transmission and its prevention.
The Journal of Infectious Diseases 03/2010; 201(8):1155-63. · 6.41 Impact Factor
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Jeanne S Mandelblatt,
Kathleen A Cronin,
Stephanie Bailey,
Donald A Berry,
Harry J de Koning,
Gerrit Draisma,
Hui Huang, Sandra J Lee,
Mark Munsell,
Sylvia K Plevritis,
Peter Ravdin,
Clyde B Schechter,
Bronislava Sigal,
Michael A Stoto,
Natasha K Stout,
Nicolien T van Ravesteyn,
John Venier,
Marvin Zelen,
Eric J Feuer
[show abstract]
[hide abstract]
ABSTRACT: Despite trials of mammography and widespread use, optimal screening policy is controversial.
To evaluate U.S. breast cancer screening strategies.
6 models using common data elements.
National data on age-specific incidence, competing mortality, mammography characteristics, and treatment effects.
A contemporary population cohort.
Lifetime.
Societal.
20 screening strategies with varying initiation and cessation ages applied annually or biennially.
Number of mammograms, reduction in deaths from breast cancer or life-years gained (vs. no screening), false-positive results, unnecessary biopsies, and overdiagnosis.
The 6 models produced consistent rankings of screening strategies. Screening biennially maintained an average of 81% (range across strategies and models, 67% to 99%) of the benefit of annual screening with almost half the number of false-positive results. Screening biennially from ages 50 to 69 years achieved a median 16.5% (range, 15% to 23%) reduction in breast cancer deaths versus no screening. Initiating biennial screening at age 40 years (vs. 50 years) reduced mortality by an additional 3% (range, 1% to 6%), consumed more resources, and yielded more false-positive results. Biennial screening after age 69 years yielded some additional mortality reduction in all models, but overdiagnosis increased most substantially at older ages.
Varying test sensitivity or treatment patterns did not change conclusions.
Results do not include morbidity from false-positive results, patient knowledge of earlier diagnosis, or unnecessary treatment.
Biennial screening achieves most of the benefit of annual screening with less harm. Decisions about the best strategy depend on program and individual objectives and the weight placed on benefits, harms, and resource considerations. Primary Funding Source: National Cancer Institute.
Annals of internal medicine 11/2009; 151(10):738-47. · 16.73 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A vaginal microbicide should prevent pathogen transmission without disrupting tissue barriers to infection. Ideally, it would not need to be applied immediately before sexual intercourse, when compliance is a problem. Intravaginal administration of small interfering RNA (siRNA) lipoplexes targeting Herpes Simplex Virus Type 2 (HSV-2) genes protects mice from HSV-2. However, protection is short-lived, and the transfection lipid on its own unacceptably enhances transmission. Here, we show that cholesterol-conjugated (chol)-siRNAs without lipid silence gene expression in the vagina without causing inflammation or inducing interferons. A viral siRNA prevents transmission within a day of challenge, whereas an siRNA targeting the HSV-2 receptor nectin-1 protects for a week, but protection is delayed for a few days until the receptor is downmodulated. Combining siRNAs targeting a viral and host gene protects mice from HSV-2 for a week, irrespective of the time of challenge. Therefore, intravaginal siRNAs could provide sustained protection against viral transmission.
Cell host & microbe 02/2009; 5(1):84-94. · 13.02 Impact Factor
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[show abstract]
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ABSTRACT: Consider a group of subjects who are offered an opportunity to receive a sequence of periodic special examinations for the purpose of diagnosing a chronic disease earlier relative to usual care. The mortality for the early detection group is to be compared with a group receiving usual care. Benefit is reflected in a potential reduction in mortality. This article develops a general probability model that can be used to predict cumulative mortality for each of these groups. The elements of the model assume (i) a four-state progressive disease model in which a subject may be in a disease-free state (or a disease state that cannot be detected), preclinical disease state (capable of being diagnosed by a special exam), clinical state (diagnosis by usual care), and a death state; (ii) age-dependent transitions into the states; (iii) age-dependent examination sensitivity; (iv) age-dependent sojourn time in each state; and (v) the distribution of disease stages on diagnosis conditional on modality of detection. The model may be used to (i) compare mortality rates for different screening schedules; (ii) explore potential benefit of subpopulations; and (iii) compare relative reductions in disease-specific mortality due to advances and dissemination of both treatment and early detection screening programs.
Biometrics 07/2008; 64(2):386-95. · 1.83 Impact Factor
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M Quinn DeGottardi,
Sharon K Lew,
Michael Piatak,
Bin Jia,
Yang Feng, Sandra J Lee,
Jason M Brenchley,
Daniel C Douek,
Toshiaki Kodama,
Jeffrey D Lifson,
David T Evans
[show abstract]
[hide abstract]
ABSTRACT: Molecular differences in the envelope glycoproteins of human immunodeficiency virus type 1 and simian immunodeficiency virus (SIV) determine virus infectivity and cellular tropism. To examine how these properties contribute to productive infection in vivo, rhesus macaques were inoculated with strains of single-cycle SIV (scSIV) engineered to express three different envelope glycoproteins with full-length (TM(open)) or truncated (TM(stop)) cytoplasmic tails. The 239 envelope uses CCR5 for infection of memory CD4(+) T cells, the 316 envelope also uses CCR5 but has enhanced infectivity for primary macrophages, and the 155T3 envelope uses CXCR4 for infection of both naive and memory CD4(+) T cells. Separate groups of six rhesus macaques were inoculated intravenously with mixtures of TM(open) and TM(stop) scSIV(mac)239, scSIV(mac)316, and scSIV(mac)155T3. A multiplex real-time PCR assay specific for unique sequence tags engineered into each virus was then used to measure viral loads for each strain independently. Viral loads in plasma peaked on day 4 for each strain and were resolved below the threshold of detection within 4 to 10 weeks. Truncation of the envelope cytoplasmic tail significantly increased the peak of viremia for all three envelope variants and the titer of SIV-specific antibody responses. Although peak viremias were similar for both R5- and X4-tropic viruses, clearance of scSIV(mac)155T3 TM(stop) was significantly delayed relative to the other strains, possibly reflecting the infection of a CXCR4(+) cell population that is less susceptible to the cytopathic effects of virus infection. These studies reveal differences in the peaks and durations of a single round of productive infection that reflect envelope-specific differences in infectivity, chemokine receptor specificity, and cellular tropism.
Journal of Virology 02/2008; 82(1):321-34. · 5.40 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Individuals living in sub-Saharan Africa represent 10% of the world's population but almost 2/3 of all HIV-1/AIDS cases. The disproportionate HIV-1 infection rates in this region may be linked to helminthic parasite infections that affect many individuals in the developing world. However, the hypothesis that parasite infection increases an individual's susceptibility to HIV-1 has never been prospectively tested in a relevant in vivo model.
We measured whether pre-existing infection of rhesus monkeys with a parasitic worm would facilitate systemic infection after mucosal AIDS virus exposure. Two groups of animals, one consisting of normal monkeys and the other harboring Schistosoma mansoni, were challenged intrarectally with decreasing doses of R5-tropic clade C simian-human immunodeficiency virus (SHIV-C). Systemic infection occurred in parasitized monkeys at viral doses that remained sub-infectious in normal hosts. In fact, the 50% animal infectious (AID(50)) SHIV-C dose was 17-fold lower in parasitized animals compared to controls (P<0.001). Coinfected animals also had significantly higher peak viral RNA loads than controls (P<0.001), as well as increased viral replication in CD4(+) central memory cells (P = 0.03).
Our data provide the first direct evidence that acute schistosomiasis significantly increases the risk of de novo AIDS virus acquisition, and the magnitude of the effect suggests that control of helminth infections may be a useful public health intervention to help decrease the spread of HIV-1.
PLoS Neglected Tropical Diseases 01/2008; 2(7):e265. · 4.69 Impact Factor
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Mila Ayash-Rashkovsky,
Agnès-Laurence Chenine,
Lisa N Steele, Sandra J Lee,
Ruijiang Song,
Helena Ong,
Robert A Rasmussen,
Regina Hofmann-Lehmann,
James G Else,
Peter Augostini,
Harold M McClure,
W Evan Secor,
Ruth M Ruprecht
[show abstract]
[hide abstract]
ABSTRACT: We tested the hypothesis that helminth parasite coinfection would intensify viremia and accelerate disease progression in monkeys chronically infected with an R5 simian-human immunodeficiency virus (SHIV) encoding a human immunodeficiency virus type 1 (HIV-1) clade C envelope. Fifteen rhesus monkeys with stable SHIV-1157ip infection were enrolled into a prospective, randomized trial. These seropositive animals had undetectable viral RNA and no signs of immunodeficiency. Seven animals served as virus-only controls; eight animals were exposed to Schistosoma mansoni cercariae. From week 5 after parasite exposure onward, coinfected animals shed eggs in their feces, developed eosinophilia, and had significantly higher mRNA expression of the T-helper type 2 cytokine interleukin-4 (P = 0.001) than animals without schistosomiasis. Compared to virus-only controls, viral replication was significantly increased in coinfected monkeys (P = 0.012), and the percentage of their CD4(+) CD29(+) memory cells decreased over time (P = 0.05). Thus, S. mansoni coinfection significantly increased viral replication and induced T-cell subset alterations in monkeys with chronic SHIV clade C infection.
Infection and Immunity 05/2007; 75(4):1751-6. · 4.16 Impact Factor
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ABSTRACT: Herpes simplex virus 2 (HSV-2) infection causes significant morbidity and is an important cofactor for the transmission of HIV infection. A microbicide to prevent sexual transmission of HSV-2 would contribute substantially to controlling the spread of HIV and other infections. Because RNA interference (RNAi) provides effective antiviral defence in plants and other organisms, several studies have focused on harnessing RNAi to inhibit viral infection. Here we show that vaginal instillation of small interfering RNAs (siRNAs) targeting HSV-2 protects mice from lethal infection. siRNAs mixed with lipid are efficiently taken up by epithelial and lamina propria cells and silence gene expression in the mouse vagina and ectocervix for at least nine days. Intravaginal application of siRNAs targeting the HSV-2 UL27 and UL29 genes (which encode an envelope glycoprotein and a DNA binding protein, respectively) was well tolerated, did not induce interferon-responsive genes or cause inflammation, and protected mice when administered before and/or after lethal HSV-2 challenge. These results suggest that siRNAs are attractive candidates for the active component of a microbicide designed to prevent viral infection or transmission.
Nature 02/2006; 439(7072):89-94. · 36.28 Impact Factor
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Christoph G Lange,
Zhan Xu,
Bruce K Patterson,
Kathy Medvik,
Brooke Harnisch,
Robert Asaad,
Hernan Valdez, Sandra J Lee,
Alan Landay,
Judy Lieberman,
Michael M Lederman
[show abstract]
[hide abstract]
ABSTRACT: To ascertain whether lymphoproliferation (LP) responses to HIVp24 in chronically infected patients treated with antiretroviral therapy (ART) predict an improved cytolytic T-cell phenotype or better in vivo immune function as measured by immunization responses.
HIV-infected patients who started ART during chronic infection and who achieved viral suppression (HIV-RNA < 400 copies/ml for > 12 months) were grouped by the presence of strong [stimulation index (SI) > 10; n = 21] or absent (SI < 3; n = 18) LP to HIV-core antigen. The two groups were compared for functional immune responses to vaccination with diphtheria-toxoid, tetanus-toxoid and keyhole-limpet-hemocyanin, frequency of circulating naive and memory CD4+ and CD8+ T lymphocytes, maturation phenotype and expression of cytolytic molecules on total and HIV-specific CD8+ T cells, and frequency of memory CD4+ T cells with intracellular HIV-mRNA. Group comparisons were analyzed by non-parametric Mann-Whitney tests. Proportions were estimated by Pearson's chi analysis.
There were no differences between the groups in immune responses to vaccination or in the numbers or phenotype of circulating T cells. In a subgroup of HLA-A2+ or B8+ patients, HIV-reactive CD8+ T cells in both groups had similar expression of perforin, granzyme A and T-cell maturation markers (CD27, CD28, CCR7, CD62L). However, patients with SI > 10 in response to HIVp24 tended to more often have high levels of circulating CD4+ T cells with intracellular HIV-1 mRNA than did patients with SI < 3.
Following long-standing suppression of viral replication on ART, the presence of HIV-1 specific T-helper proliferation responses does not correlate with improved indices of immune phenotype or function but may reflect relatively higher levels of HIV-expression.
AIDS 03/2004; 18(4):605-13. · 6.24 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Despite the frequency of HIV-specific CD8 T cells, most HIV-infected patients do not control viral replication without antiviral drugs. Although CD8 T cells are important in containing acute HIV and simian immunodeficiency virus (SIV) infection, CD8 T-cell functions are compromised in chronic infection. To investigate whether functional deficits are specific to HIV, the phenotypic and functional properties of HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV)-specific CD8 T cells, labeled with HLA A2.1 or B8 tetramers, were compared in 35 HIV-infected and 9 healthy donors. Cytotoxic T lymphocytes express the cytolytic molecules perforin and granzymes, and are thought to be CD45RA(+)CD27(-). Although most HIV- specific cells are antigen experienced and express granzyme A (median, 85%), few express high levels of perforin (median, 10%) or CD45RA (median, 14%) or have down-modulated CD27 (median, 12%). Perforin expression by HIV-specific cells is not significantly different from that of EBV- or CMV-specific cells in the same donors or in healthy donors. EBV- and CMV-specific cells, like HIV-specific cells, are often not cytotoxic when tested directly ex vivo. HIV-specific T-cell expression of other phenotypic markers is similar to that of EBV- and CMV-specific CD8 T cells in healthy donors. However, CMV-specific cells (and, to a lesser extent, EBV-specific cells) in HIV-infected donors are more likely to be CD27(-), CD45RA(+), and GzmA(+). These results suggest that the chance to eradicate an infection by T-cell-mediated lysis may be undermined once an infection becomes chronic. Impaired antiviral cytotoxicity during chronic infection is not specific to HIV but likely represents the immune response to chronic antigenic exposure.
Blood 02/2003; 101(1):226-35. · 9.90 Impact Factor
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Cancer treatment and research 02/2002; 113:19-36.
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Cancer treatment and research 02/2002; 113:1-18.
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ABSTRACT: We propose a Bayesian formulation of the sample size problem for planning clinical trials. The frequentist paradigm for calculating sample sizes for clinical trials is to prespecify the type I and II error probabilities. These error probabilities are conditional on the true hypotheses. Instead we propose prespecifying posterior probabilities which are conditional on the outcome of the trial. Our method is easy to implement and has intuitive interpretations. We illustrate an application of our method to the planning of cancer clinical trials for the Eastern Cooperative Oncology Group (ECOG).
